Next Steps in Myeloma Include Combo Regimens and Achieving MRD

Over the last couple of years, a variety of new therapeutic options have emerged for patients with multiple myeloma. Moreover, even with the recent FDA approvals of the monoclonal antibodies daratumumab (Darzalex) and elotuzumab (Empliciti), as well as the oral proteasome inhibitor ixazomib (Ninlaro), other agents and approaches that have been a staple in the paradigm will continue to have pivotal roles.

For example, the immunomodulatory agent lenalidomide (Revlimid) was initially granted FDA approval for use with dexamethasone in patients with multiple myeloma who received at least 1 prior therapy. The indication was expanded in 2015 for use in combination with dexamethasone to include newly diagnosed patients who are not eligible for autologous stem cell transplant (ASCT).

Lenalidomide’s indication was expanded again in February 2017 when the FDA approved it as a maintenance therapy following ASCT. But clinical trials are studying the agent in combination as maintenance regimens and in other settings to further advance long-term outcomes.

A phase III randomized trial is exploring the triplet therapy of carfilzomib (Kyprolis), lenalidomide, and dexamethasone versus lenalidomide alone after ASCT for patients who are considered eligible for lenalidomide maintenance (NCT02659293). Researchers will compare progression-free survival (PFS) and the rate of minimal residual disease (MRD) negativity.

Additionally, the combination of lenalidomide and the PD-1 inhibitor pembrolizumab (Keytruda) is being tested in a phase II trial for patients with high-risk multiple myeloma following high-dose chemotherapy with ASCT (NCT02906332).

Ruben Niesvizky, MD, lectured on the evolving paradigm of multiple myeloma during the 2017 OncLive State of the Science Summit on Hematologic Malignancies. In an interview during the meeting, Niesvizky, who is director of the Multiple Myeloma Center at Weill Cornell Medicine/NewYork-Presbyterian Hospital, spoke about some of the exciting advances, the potential of chimeric antigen receptor (CAR) T-cell therapy, and emerging combination regimens on the horizon.

OncLive: What were the highlights from your presentation on multiple myeloma?

Niesvizky: It was a pleasure to be here. The most important point I wanted to make is that there has been a large evolution in the management of patients with multiple myeloma. We have tried to change the algorithms to achieve the best response possible, even in people who have developed the CRAB criteria. We are moving toward chemoprevention and early intervention in people who have not developed active disease. This has been allowed using criteria that includes high free light chain ratio, high level of bone marrow plasma cytosis, or the presence of abnormalities in an MRI. With that, we can start doing early intervention—as already published with lenalidomide/dexamethasone, or as we are moving in the future to using more aggressive induction consolidation and maintenance type of programs. We are about to use protocols in that arena.

The second thing is that induction has also changed, and now we are changing the goals of remission. It is to not only to achieve complete remission (CR) but to achieve MRD. With MRD, you can hope for the best and longest type of PFS and overall survival. We can even start exploring potential curative therapies. We are also exploring the new data available for transplant, which remains an important tool to achieve that MRD but is not seen as [necessary]. Therefore, we can still achieve an MRD state without transplant. I utilize transplant later in the disease as a salvage therapy. It is important to still collect stem cells and do transplant in those patients who could not achieve a CR.

We are also seeing difficulties in trying to identify precision medicine vectors to initiate therapy, because multiple myeloma carries a large genomic instability and we cannot identify 1 simple gene to target. We are busy incorporating monoclonal antibodies into therapy, including daratumumab and others that can enhance the ability to achieve MRD either in the frontline or relapsed setting.

Even if you achieve an MRD state, it is still standard of care to use maintenance therapy. Currently, the standard is with lenalidomide but we are exploring it in combination with other agents, which include proteasome inhibitors, such as ixazomib (Ninlaro), or even possibly with oprozomib.